Article
Chemistry, Medicinal
Manon Sturbaut, Fabrice Bailly, Mathilde Coevoet, Pasquale Sileo, Martine Pugniere, Maxime Liberelle, Romain Magnez, Xavier Thuru, Marie-Christine Chartier-Harlin, Patricia Melnyk, Muriel Gelin, Frederic Allemand, Jean-Francois Guichou, Philippe Cotelle
Summary: The Hippo pathway regulates organ size and tissue homeostasis through controlling cell growth, proliferation, and apoptosis. Dysregulation of YAP, TAZ, and TEADs in cancer makes YAP/TAZ-TEAD interaction a new emerging anti-cancer target. Compound 6 is the first inhibitor of YAP/TAZ-TEAD targeting interface 2 and has the potential to inhibit cell proliferation.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2021)
Article
Biochemistry & Molecular Biology
Esther J. Han, Seoung Rak Lee, Shotaro Hoshino, Mohammad R. Seyedsayamdost
Summary: Microorganisms have been a valuable source of therapeutically important natural products. This study utilized high-throughput elicitor screening to uncover cryptic metabolites with antiproliferative activity, leading to the discovery of novel bioactive compounds. These findings demonstrate the untapped potential of microbial strains in providing new molecules for cancer treatment.
ACS CHEMICAL BIOLOGY
(2022)
Article
Chemistry, Multidisciplinary
Nir Hananya, Sara K. Daley, John D. Bagert, Tom W. Muir
Summary: The study developed a efficient semi-synthesis method to create full-length ADP-ribosylated histones H3 and H2B, which were used to investigate the roles of histone ADP-ribosylation in DNA damage response. The results showed that ADP-ribosylation of serine-6 of histone H2B inhibits chromatin folding and higher-order organization, providing new insights into the impact of histone modifications on chromatin structure.
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
(2021)
Article
Chemistry, Medicinal
Hengzhi Sun, Jinzheng Wang, Shengjie Liu, Xinyu Zhou, Liang Dai, Caiping Chen, Qinglong Xu, Xiaoan Wen, Keguang Cheng, Hongbin Sun, Haoliang Yuan
Summary: A potential binding pocket was identified on the PCSK9-LDLR PPI surface by induced-fit docking, leading to the discovery of novel small molecule inhibitors through virtual screening and biological evaluations. Compound 13 showed inhibitory activity against PCSK9-LDLR PPI and restored LDLR uptake function in HepG2 cells, indicating its potential as a lead compound for further development of small molecule inhibitors targeting PCSK9-LDLR PPI.
JOURNAL OF CHEMICAL INFORMATION AND MODELING
(2021)
Article
Biochemistry & Molecular Biology
Jianxiang Huang, Kevin C. C. Chan, Ruhong Zhou
Summary: The emergence of SARS-CoV-2 has caused a global alarm, leading to extensive research on repurposing drugs to treat the infection. Researchers have found that a metabolite of the drug fenofibrate, called fenofibric acid (FA), can destabilize the receptor-binding domain (RBD) of the viral spike protein, inhibiting its binding to the hACE2 receptor. Through molecular dynamics simulations, the study identified a potential cryptic binding site for FA on the RBD and demonstrated that FA alters the conformation of the binding loop, reducing its affinity for ACE2. This research provides new insights for designing SARS-CoV-2 inhibitors targeting cryptic sites on the RBD.
Article
Multidisciplinary Sciences
Itai Sharon, Sharon Pinus, Marcel Grogg, Nicolas Moitessier, Donald Hilvert, T. Martin Schmeing
Summary: Cyanophycin synthetase CphA1 is capable of synthesizing cyanophycin without exogenous primers, utilizing a cryptic metallopeptidase-like active site in its N-terminal domain to digest cyanophycin into primers. Primer dependence of CphA1 in heterologous hosts may be a limiting factor for cyanophycin production.
NATURE COMMUNICATIONS
(2022)
Article
Biochemistry & Molecular Biology
Suzanne OConnor, Yann-Vai Le Bihan, Isaac M. Westwood, Manjuan Liu, Oi Wei Mak, Gabriel Zazeri, Ana P. R. Povinelli, Alan M. Jones, Rob van Montfort, Johannes Reynisson, Ian Collins
Summary: In this study, the researchers explored the potential for inhibiting HSP70 through alternative binding sites. They identified a cryptic binding site in the nucleotide-binding domain of HSP70 and confirmed fragment binding using various methods. The study also discovered five compounds that bind to HSP70. These findings provide new opportunities for developing ATP-competitive inhibitors targeting HSP70.
Article
Chemistry, Medicinal
Niu Zhang, Zhicheng Zuo
Summary: The discovery of small-molecule Cas9 inhibitors provides a feasible approach to regulate CRISPR-Cas9 activity. Through computational analysis, a ligand binding site was identified within the carboxyl-terminal domain (CTD) of Cas9, which plays a role in recognizing the protospacer adjacent motif (PAM). Binding of the inhibitor BRD0539 induced structural rearrangements in the CTD, leading to the inhibition of Cas9 function. This study offers insights into the development of safer CRISPR-Cas9 technologies through improving existing ligands and discovering novel small-molecule brakes.
JOURNAL OF CHEMICAL INFORMATION AND MODELING
(2023)
Article
Oncology
Shuo Chen, Jia-Le Wu, Ying Liang, Yi-Gang Tang, Hua-Xin Song, Li-Li Wu, Yang-Fei Xing, Ni Yan, Yun-Tong Li, Zheng-Yuan Wang, Shu-Jun Xiao, Xin Lu, Sai-Juan Chen, Min Lu
Summary: The study identified small molecules, such as arsenic trioxide, as compounds that can rescue the structural mutations in p53, reactivating its tumor suppressive function. Arsenic binding stabilizes the DNA-binding loop-sheet-helix motif and overall beta-sandwich fold, providing a new strategy for cancer therapy targeting p53 mutations.
Article
Biochemical Research Methods
Phorutai Pearngam, Sira Sriswasdi, Trairak Pisitkun, Andrew R. Jones
Summary: MHC-peptide binding prediction is crucial for understanding immune responses and developing immunotherapeutics. Introducing global FDR and PEP estimation provides a more reliable evaluation of predicted results. MHCVision offers a better balance between sensitivity and precision in comparison to using traditional threshold values.
Article
Chemistry, Multidisciplinary
Duan Ni, Jiacheng Wei, Xinheng He, Ashfaq Ur Rehman, Xinyi Li, Yuran Qiu, Jun Pu, Shaoyong Lu, Jian Zhang
Summary: Allostery is a direct and efficient method for fine-tuning protein functions, gaining recognition in drug discovery. Identifying allosteric sites is a challenge for drug design, with recent studies revealing bidirectional allosteric coupling and reversed communication between orthosteric and allosteric sites. A new framework combining computational and experimental strategies has been proposed for predicting allosteric sites, demonstrating desirable performance in identifying potential cryptic sites for allosteric drug design.
Article
Biochemistry & Molecular Biology
Mohamed Hagras, Moshira A. El Deeb, Heba S. A. Elzahabi, Eslam B. Elkaeed, Ahmed B. M. Mehany, Ibrahim H. Eissa
Summary: Newly synthesized quinoline derivatives exhibited superior cytotoxic activities and inhibitory effects against tubulin polymerisation in human cancer cell lines, potentially serving as promising anticancer agents.
JOURNAL OF ENZYME INHIBITION AND MEDICINAL CHEMISTRY
(2021)
Article
Multidisciplinary Sciences
Florian C. Boucher, Cedric Dentant, Sebastien Ibanez, Thibaut Capblancq, Marti Boleda, Louise Boulangeat, Jan Smycka, Cristina Roquet, Sebastien Lavergne
Summary: Through plant surveys and genomic research, this study found that plant diversity in high-elevation temperate mountains was enriched during the Pleistocene, driven by the combined action of geography and geology.
SCIENTIFIC REPORTS
(2021)
Article
Chemistry, Multidisciplinary
Jun Shi Chang, Alexander A. Vinogradov, Yue Zhang, Yuki Goto, Hiroaki Suga
Summary: A deep learning model was used to streamline the design of mRNA display libraries, leading to the discovery of potent thiopeptide ligands with favorable pharmacological properties against IRAK4 kinase and TLR10 cell surface receptor.
ACS CENTRAL SCIENCE
(2023)
Article
Biochemistry & Molecular Biology
Tao Zhang, Xu Pang, Jianyuan Zhao, Zhe Guo, Wenni He, Guowei Cai, Jing Su, Shan Cen, Liyan Yu
Summary: This study successfully manipulated the fungus Aspergillus sp. CPCC 400735 to activate the downregulated metabolic pathway encoded by the biosynthetic gene cluster asp through overexpression of the transcriptional regulator AspE. 13 asperphenalenone derivatives, including 11 new compounds, were isolated and characterized from the mutant extracts, showing significant anti-influenza A virus effects with IC values of 0.45-2.22 μM. The identification of these compounds sheds light on the biosynthesis of asperphenalenones and could benefit downstream combinatorial biosynthesis studies.
ACS CHEMICAL BIOLOGY
(2022)